This invention relates to new compounds, pharmaceutical compositions and diagnostic kits comprising such compounds, and methods of using such compounds for inhibiting NAALADase enzyme activity, detecting diseases where NAALADase levels are altered, effecting neuronal activity, effecting TGF-xcex2 activity, inhibiting angiogenesis, and treating glutamate abnormalities, diabetic neuropathy, pain, compulsive disorders, prostate diseases, cancers and glaucoma.
The NAALADase enzyme, also known as prostate specific membrane antigen (xe2x80x9cPSMxe2x80x9d or xe2x80x9cPSMAxe2x80x9d) and human glutamate carboxypeptidase II (xe2x80x9cGCP IIxe2x80x9d), catalyzes the hydrolysis of the neuropeptide N-acetyl-aspartyl-glutamate (xe2x80x9cNAAGxe2x80x9d) to N-acetyl-aspartate (xe2x80x9cNAAxe2x80x9d) and glutamate. Based upon amino acid sequence homology, NAALADase has been assigned to the M28 family of peptidases.
Studies suggest NAALADase inhibitors may be effective in treating ischemia, spinal cord injury, demyelinating diseases, Parkinson""s disease, Amyotrophic Lateral Sclerosis (xe2x80x9cALSxe2x80x9d), alcohol dependence, nicotine dependence, cocaine dependence, cancer, diabetic neuropathy, pain and schizophrenia, and in inhibiting angiogenesis. In view of their broad range of potential applications, a need exists for new NAALADase inhibitors and pharmaceutical compositions comprising such compounds.
This invention relates to a compound of formula I 
or a pharmaceutically acceptable equivalent of said compound, wherein:
R1, R2, R3, R4, R5, R6, R7 and R8 are independently hydrogen or C1-C3 alkyl;
A1, A2, A3 and A4 are independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halo, nitro, phenyl, phenoxy, benzyl, benzyloxy or xe2x80x94COOH, or any adjacent two of A2, A3 and A4 form with the benzene ring a fused 5- or 6-membered carbocyclic or heterocyclic aromatic ring, said heterocyclic aromatic ring containing 1 or 2 oxygen, nitrogen and/or sulfur heteroatom(s).
This invention further relates to a compound of formula II 
or a pharmaceutically acceptable equivalent of said compound, wherein:
R1, R2, R3, R4, R5, R6, R7 and R8 are independently hydrogen or C1-C3 alkyl; and
A1, A2, A3, A4 and A5 are independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C3 perhaloalkyl, phenyl, phenoxy, benzyl, benzyloxy, hydroxy, halo, cyano, nitro, xe2x80x94SO2R9, xe2x80x94(Cxe2x95x90O)NR9R10, xe2x80x94(Cxe2x95x90O)NR9(CH2)nCOOH, xe2x80x94NR9(Cxe2x95x90O)R10, xe2x80x94(CH2)nCOOH or xe2x80x94COOH, or any adjacent two of A1, A2, A3, A4 and A5 form with the benzene ring a fused 5- or 6-membered carbocyclic or heterocyclic aromatic ring, said heterocyclic aromatic ring containing 1 or 2 oxygen, nitrogen and/or sulfur heteroatom(s);
R9 and R10 are independently hydrogen, C1-C6 alkyl, phenyl or benzyl; and
n is 1-3;
provided that if A1, A3 and A5 are independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halo, nitro, phenyl, phenoxy, benzyl, benzyloxy or xe2x80x94COOH, then neither A2 nor A4 are xe2x80x94COOH; and provided that if any adjacent two of A3, A4 and A5 form with the benzene ring a fused 5- or 6-membered carbocyclic or heterocyclic aromatic ring, said heterocyclic aromatic ring containing 1 or 2 oxygen, nitrogen and/or sulfur heteroatom(s), then A2 is not xe2x80x94COOH.
This invention also relates to a compound of formula III 
or a pharmaceutically acceptable equivalent of said compound, wherein:
X and Y are independently xe2x80x94CR5R6xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94NRxe2x80x94, provided that at least one of X and Y is/are xe2x80x94CR5R6xe2x80x94;
A1, A2, A3, A4 and A5 are independently hydrogen, C1-C9 alkyl, C2-C9 alkenyl, C2-C9 alkynyl, aryl, heteroaryl, carbocycle, heterocycle, C1-C9 alkoxy, C2-C9 alkenyloxy, phenoxy, benzyloxy, hydroxy, halo, nitro, cyano, isocyano, xe2x80x94COOR7, xe2x80x94COR7, xe2x80x94NR7R8, xe2x80x94SR7, xe2x80x94SOR7, xe2x80x94SO2R7, xe2x80x94SO2(OR7), xe2x80x94(Cxe2x95x90O)NR7R8, xe2x80x94(Cxe2x95x90O)NR7(CH2)nCOOH, xe2x80x94NR7(Cxe2x95x90O) R8 or xe2x80x94(CH2)nCOOH, or any adjacent two of A1, A2, A3, A4 and A5 form with the benzene ring a fused ring that is saturated or unsaturated, aromatic or non-aromatic, and carbocyclic or heterocyclic, said heterocyclic ring containing 1 or 2 oxygen, nitrogen and/or sulfur heteroatom(s);
n is 1-3;
R, R1, R2, R3, R4, R5, R6, R7 and R8 are independently hydrogen, C1-C9 alkyl, C2-C9 alkenyl, C2-C9 alkynyl, aryl, heteroaryl, carbocycle or heterocycle; and
said alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocycle, heterocycle, alkoxy, alkenyloxy, phenoxy, benzyloxy, and fused ring are independently unsubstituted or substituted with one or more substituent(s);
provided that if A1, A2 and A3 are each hydrogen, and A4 and A5 are each xe2x80x94COOH, then A4 is ortho to A5; and provided that if Y is xe2x80x94CR5R6xe2x80x94, then at least one of A1, A2, A3, A4 and A5 is/are independently phenoxy, benzyloxy, aryl, heteroaryl, carbocycle or heterocycle that is substituted with one or more substituent(s).
Additionally, this invention relates to method for inhibiting NAALADase enzyme activity, treating a glutamate abnormality, effecting a neuronal activity, treating a prostate disease, treating cancer, inhibiting angiogenesis or effecting a TGF-xcex2 activity, comprising administering to a mammal in need of such inhibition, treatment or effect, an effective amount of a compound of formula I, II or III, as described above.
This invention further relates to method for detecting a disease, disorder or condition where NAALADase levels are altered, comprising:
(i) contacting a sample of bodily tissue or fluid with a compound of formula I, II or III, as defined above, wherein said compound binds to any NAALADase in said sample; and
(ii) measuring the amount of any NAALADase bound to said sample, wherein the amount of NAALADase is diagnostic for said disease, disorder or condition.
This invention also relates to a method for detecting a disease, disorder or condition where NAALADase levels are altered in an animal or a mammal, comprising:
(i) labeling a compound of formula I, II or III, as defined above, with an imaging reagent;
(ii) administering to said animal or mammal an effective amount of the labeled compound;
(iii) allowing said labeled compound to localize and bind to NAALADase present in said animal or mammal; and
(iv) measuring the amount of NAALADase bound to said labeled compound, wherein the amount of NAALADase is diagnostic for said disease, disorder or condition.
Additionally, this invention further relates to a diagnostic kit for detecting a disease, disorder or condition where NAALADase levels are altered, comprising a compound of formula I, II or III, as defined above, labeled with a marker.
Finally, this invention relates to a pharmaceutical composition comprising:
(i) an effective amount of a compound of formula I, II or III, as described above; and
(ii) a pharmaceutically acceptable carrier.